Alzheimer's disease (AD) affects an estimated 5.4 million Americans costing the society more than $160 billion annually, and this figure is expected to triple by the middle of the century. This emphasizes the urgent need for efficacious therapies for the treatment, delay of progression, or prevention of AD. A major proinflammatory molecule which levels are increased in the AD brain is TNF alpha (TNF?). Preliminary data obtained after administration of high doses of the TNF? antagonist thalidomide to APP23 transgenic mice showed decreased brain TNF? levels, plaque number, and amyloid beta loads. These data were the basis to conduct an NIA-sponsored human AD pilot study with thalidomide at our clinical research center. However, patients on high doses of thalidomide experience pronounced adverse events. This led us to search for safer and less toxic alternatives for chronic administration for AD treatment, and we identified the FDA-approved anti-cancer drug lenalidomide as a very promising candidate. We hypothesize that lenalidomide can significantly decrease AD-like neuropathology by modulating chronic inflammation and BACE1 levels. Overall, our project is designed to 1- identify the most efficient regimen to reduce chronic brain inflammation and amyloid burden; 2- assess the potency of lenalidomide to treat tau pathology independently and in presence of A deposits; and 3- dissect the main molecular mechanisms underlying lenalidomide-mediated reduction in AD-like pathology. To reach these goals, we will use a combination of AD transgenic mouse models and extensive cell culture work. If successful, our project will provide critical information regarding the potential of lenalidomide t treat AD. Since lenalidomide is FDA-approved for human malignancies treatment, repurposing this drug would help provide the pre-clinical underpinnings for translation into clinical trials aiming at using patient-acceptable regimens. We strongly believe that the combination of the PI, mentors, consultants, and the environment are perfectly fitted for this career development award project. The PI is a young neuroscientist with a very good publication record and is extremely motivated by this project that will continue to develop a very promising career in drug pre-clinica development related neuronal disorders. In addition, the project will provide him a path towards independence. His mentors are experts in Alzheimer's mouse models (Dr. Oddo), and in clinical diagnosis of neuronal disorders and clinical trials (Dr. Sabbagh and Dr. Reiman). Along with Drs. Coleman, Lahiri, and Chen, they will teach new techniques and working methods to the PI. The in-house training will be completed by attending international trainings in drug discovery and development, as well as scientific meetings. Banner Research is fully supportive of this application. Collectively, all the factors are assembled for the success of the project which is highly significant to the NIA's mission, and for the development of the PI as an independent scientist who will apply first hand all the training associated with this award throughout his career.